The delivery of drugs through skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and non-invasive way of administering drugs. The variable rates of absorption and metabolism in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the bloodstream of lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs.
To increase skin permeability, an in particular, to increase the permeability of the stratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be transdermally administered), the skin may be treated with one or more permeation enhancing agents (or "permeation enhancers", as sometimes referred to herein) prior to administration of the drug. Alternatively, and preferably, the drug and permeation enhance are simultaneously applied or co-delivered.
Various such compounds for enhancing the permeability of skin are known in the art. U.S. Pat. Nos. 4,006,218, 3,551,554 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of topically applied drugs through the stratum corneum. Other compounds which have been used to enhance skin permeability include: decylmethylsufloxide (C.sub.10 MSO); polyethylene glycol monolaurate (PEGML; see e.g., U.S. Pat. No. 4,568,343; the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecyl-cyclazacycloheptan-2-one (available under the trademark "Azone" from Nelson Research & Development Co., Irvine, CA; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); "cell envelope disordering" compounds such as methyl laurate or oleic acid in combination with solvents such as N-2-hydroxyethyl) pyrrolidone (U.S. Pat. No. 4,537,776) or C.sub.3 -C.sub.4 diols (U.S. Pat. No. 4,552,872, EPA 043738). U.S. Pat. No. 4,593,048 also discloses a composition stated to promote drug adsorption by the skin, the composition containing a major amount of a lower alcohol and lesser amounts of various 6-24C hydrocarbons.
The disadvantage of using many permeation enhancers is that they are often quite irritating to the skin. Attempts to reduce the skin irritation that results from permeation enhancers have not proven very successful. The inventors herein have now provided a solution to the problem, by virtue of having discovered that glycerin is effective as a topical anti-irritant in reducing skin irritation from generally mildly to moderately irritating drug/permeation enhancer combinations. However, the terms "mildly" and "moderately" are relative terms and the invention may function equally well in certain "severely" irritating drug/permeation enhancer combinations.
Glycerin is well known as an emollient, such as taught in U.S. Pat. No. 4,687,481, and is used in the manufacture of cosmetics and soaps. However, applicants are unaware of any teaching in the art to the effect that glycerin is an effective anti-irritant when administered in combination with a wide variety of irritation producing drug/permeation enhancer compositions. In fact, when glycerin is applied to rectal tissues for use as a laxative in children, it is stated to cause dehydration of mucosal tissues to produce an irritant effect. Physicians Desk Reference, 41st Edition, Medical Economics Company, Oradel, N.J. 1987, p. 931.
The following references provide a general overview of anti-irritants: J. P. Guillot et al., Int. Journal of Cosmetic Sci. 5:255-265 (1983); R. L. Goldemberg, "Antiirritants" in Principles of Cosmetics for the Dermatologist, Phillip Frost & Stephen N. Horwitz, eds., London: The C.V. Mosby Company, 1979; R. L. Goldemberg, J. Soc. Cosmet. Chem. 30:415-427 (Dec. 1979); and U.S. Pat. No. 4,695,456 to Wilder (summarizes theories relating to the processes involved in chemical irritant injury). The Guillot et al. paper is particularly relevant here, as it teaches that glycerin is ineffective as an anti-irritant (id. at p. 263), contrary to applicants' present discovery.